Contrast agents, or contrast media, are substances that can alter the way in which a region is analyzed in medical imaging. In particular, they are able to change the contrast of an organ, an injury, or any other surrounding structure, to make visible such details that otherwise would be difficult to detect or appreciate.
Contrast agents are primarily used in the radiological or in the nuclear magnetic resonance diagnostic fields. Depending on the field of application, these derivatives present structural features, such as, in the case of molecules useful as contrast agents for X-rays analysis, the presence of one or more atom with high atomic number (e.g. iodine or barium).
Iopamidol (N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide) (II), whose structural formula is indicated below, is one of the numerous tri-iodinated diagnostic agents, commercially available and widely used for this purpose:

The widespread use of this compound in diagnostics makes necessary for the manufacturers to dispose of easy and convenient syntheses on an industrial scale.
Iopamidol and its synthesis were first disclosed in GB1472050.
Several synthetic approaches have been since then described: they are mostly characterised by the conversion of aromatic amino derivatives into the corresponding carboxamides, by reaction with a suitable α-hydroxyacid derivative, see for instance: WO 02/44132, WO02/44125, WO 96/37459, WO 96/37460, U.S. Pat. No. 5,362,905, WO 97/47590, WO 98/24757, WO 98/28259 and WO 99/58494.
5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide (V) is a key intermediate in the synthesis of Iopamidol. As shown in Scheme 1 below where prior art synthesis has been summarized, its iodination gives the intermediate 5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV) which may be further reacted with suitable acylating agents, such as acetic anhydride in order to protect the hydroxyl groups (as described, i.e. in WO 02/44132 or in WO00/050385) and prevent their reaction with N—(S)-2-(acetyloxy)propanoyl chloride (2-acetyloxypropanoyl chloride) in the subsequent reaction. By acetylating the more reactive carboxamido-hydroxy groups, the use of an excess of 2-acetyloxypropanoyl chloride is avoided. However, the protective group, after the final deprotection with NaOH, is lost and cannot be recycled.

Furthermore, in order to protect the hydroxyl groups, an excess of acetic anhydride is required and its presence in the mixture is incompatible in the next reaction step. Subsequently, additional precipitation and crystallization steps are required.
The main drawback of this approach is related to the isolation of the intermediate (VI), to obtain the solid in a suitable crystalline form. This procedure may lead to a loss of 10% in the yield.
There is the need of an economical synthesis of Iopamidol, in particular a synthesis allowing the recovery and recycle of the reactant used as hydroxyl protective group.
There is also the need to provide a synthesis, which, at least in the last steps, allows a one-pot series of reactions in order to avoid the isolation of intermediate compounds and to increase the overall yield.
Furthermore, reactants recovery, together with a decreased waste production and disposal represent highly desirable tasks in view of a positive final reaction balance.
Boron derivatives are known as protective agents in chemical synthesis.
GB2331098 and HR Bjørsvik, H Priebe, J Cervenka, A W Aabye, T Gulbrandsen and AC Bryde (A Selective Process for N-Alkylation in Competition with O-Alkylation: Boric Acid, Borax, and Metaborate as a Cheap and Effective Protecting Group Applicable for Industrial-Scale Synthetic Processes; Organic Process Research and Development 2001, 5, 472-478) disclose a process for N-alkylation of compounds containing 1,2 and/or 1,3 diol structures. Iodinated contrast agents are disclosed as particular embodiment. In order to avoid competing O-alkylation, this document teaches the use of boron oxyacid as diol protecting agents. Salts and esters can also be used. The reaction involving diol protection by the boron oxyacid is carried out in water. After the N-alkylation reaction has come to accomplishment, diol deprotection is carried out.
Another different use of boric oxyacids in connection with iodinated contrast media is disclosed in Journal of Hazardous Materials 205-206 (2012) 10-16 (I Rustighia, I Donatia, M Ferluga, C Campa, AE Pasqua, M Rossi, S Paoletti; Borate complexes of X-ray iodinated contrast agents: Characterization and sorption studies for their removal from aqueous media). The Authors show an effective use of boric oxyacids as a means for removing iodinated contrast media from wastewater. This adduct has a good stability at alkaline pH and is adsorbed on the ionic resin Dowex 1×4, from which it is desorbed by means of a number of desorbing agents, mainly salts.